In the years since my laboratory at the NIDA IRP identified the sigma-1 receptor in 1982, many preclinical studies have shown that sigma-1 receptors and associated ligands are involved in stroke, amnesia, depression, cancer, Alzheimers disease, pain, and cocaine addiction. In this fiscal year, we found that a transcription factor Znf179 can interact with the sigma-1 receptor. Further, we found that the enhanced acetylation of Znf179 by treating cells with a histone deacetylase enzyme inhibitor SAHA can protect cells against oxidative stress. Thus, the action of the sigma-1 receptor may involve the activity of the histone deacetylase enzyme. In another report, we found that cocaine can increase axon extension in primary cortical neurons in a dopamine transporter-independent manner. Further, by reviewing past literatures, we conclude that cocaine, like many other abused drugs, works on neurons in a non-canonical fashion by targeting proteins inside of a neuron. Further investigation on the interaction of drugs of abuse with those non-canonical targets may help assist for a more complete understanding of the action of drugs of abuse.